Siponimod (BAF312) penetrates, distributes, and acts in the central nervous system: Preclinical insights

Background Siponimod (BAF312), a selective S1P1/S1P5 agonist, reduces disability progression in secondary progressive MS. Recent observations suggest it could act via S1P1/S1P5-dependent anti-inflammatory and pro-myelination effects on CNS-resident cells. Objective Generate preclinical evidence confirming siponimod's CNS penetration and activity. Methods Siponimod's CNS penetration and distribution was explored in rodents and non-human primates (NHPs) using: Liquid Chromatography coupled to tandem Mass Spectrometry (LC-MS/MS), quantitative whole-body autoradiography (QWBA) using 14C-radiolabeled siponimod or non-invasive single-photon emission CT (SPECT) with a validated 123I-radiolabeled siponimod analog. Functional CNS activity was investigated by S1P1 receptor quantification in brain homogenates. Results In mice/rats, siponimod treatments achieved dose-dependent efficacy and dose-proportional increase in drug blood levels, with mean brain/blood drug-exposure ratio (Brain/BloodDER) of 6–7. Efficacy in rat brain tissues was revealed by a dose-dependent reduction in brain S1P1 levels. QWBA distribution analysis in rats indicated that [14C]siponimod related radioactivity could readily penetrate CNS, with particularly high uptakes in white matter of cerebellum, corpus callosum, and medulla oblongata versus lower exposures in other areas such as olfactory bulb. SPECT monitoring in NHPs revealed CNS distribution with a brain/bloodDER of ∼6, as in rodents. Conclusion Findings demonstrate siponimod's CNS penetration and distribution across species, with high translational potential to human.

Quantitative bone single-photon emission CT/CT parameters reflect pain and functional status of symptomatic basal joint arthritis of the thumb

Aims The aim of this study was to assess arthritis of the basal joint of the thumb quantitatively using bone single-photon emission CT/CT (SPECT/CT) and evaluate its relationship with patients’ pain and function. Methods We retrospectively reviewed 30 patients (53 hands) with symptomatic basal joint arthritis of the thumb between April 2019 and March 2020. Visual analogue scale (VAS) scores for pain, grip strength, and pinch power of both hands and Patient-Rated Wrist/Hand Evaluation (PRWHE) scores were recorded for all patients. Basal joint arthritis was classified according to the modified Eaton-Glickel stage using routine radiographs and the CT scans of SPECT/CT, respectively. The maximum standardized uptake value (SUVmax) from SPECT/CT was measured in the four peritrapezial joints and the highest uptake was used for analysis. Results According to Eaton-Glickel classification, 11, 17, 17, and eight hands were stage 0 to I, II, III, and IV, respectively. The interobserver reliability for determining the stage of arthritis was moderate for radiographs (k = 0.41) and substantial for CT scans (k = 0.67). In a binary categorical analysis using SUVmax, pain (p < 0.001) and PRWHE scores (p = 0.004) were significantly higher in hands with higher SUVmax. Using multivariate linear regression to estimate the pain VAS, only SUVmax (B 0.172 (95% confidence interval (CI) 0.065 to 0.279; p = 0.002) showed a significant association. Estimating the variation of PRWHE scores using the same model, only SUVmax (B 1.378 (95% CI, 0.082 to 2.674); p = 0.038) showed a significant association. Conclusion The CT scans of SPECT/CT provided better interobserver reliability than routine radiographs for evaluating the severity of arthritis. A higher SUVmax in SPECT/CT was associated with more pain and functional disabilities of basal joint arthritis of the thumb. This approach could be used to complement radiographs for the evaluation of patients with this condition. Cite this article: Bone Joint J 2021;103-B(8):1380–1385.

Parathyroid Scintigraphy

The visualization of abnormal parathyroid glands is difficult due to their variations in number and localization. Noninvasive parathyroid imaging studies include 99mTc-sestamibi scintigraphy, ultrasonography, computed tomography scanning, magnetic resonance imaging, and positron emission tomography. There is a general consensus that the most sensitive and specific imaging modality, especially when it is combined with single-photon emission CT is the scintigraphy with 99mTc-sestamibi or 99mTc-tetrofosmin. 99mTc-sestamibi scintigraphy significantly increases the role of preoperative scintigraphy in patients with hyperparathyroidism and allows unilateral surgical approach with minimally invasive parathyroidectomy to be used. Generally, three protocols with the use of two radiopharmaceuticals, 99mTc-sestamibi or 99mTc-tetrofosmin, are most widely applied: single-phase dual-isotope subtraction, dual-phase single-isotope and combination of both. Each one of them has specific advantages and disadvantages. While single parathyroid adenomas are localized with greater precision, hyperfunctioning parathyroid hyperplastic cells represent a real challenge to the imaging modalities. Several factors can influence the radionuclide uptake in pathologically changed parathyroid cells, like the size, the level of their functional activity, the quantity of oxyphilic cells, mitochondria, P glycoprotein and other MDR gene products.

Crossed cerebellar diaschisis after stroke detected noninvasively by arterial spin-labeling MR imaging

Background As a noninvasive perfusion-weighted MRI technique, arterial spin-labeling (ASL) was becoming increasingly used to evaluate cerebral hemodynamics in many studies. The relation between ASL-MRI and crossed cerebellar diaschisis (CCD) was rarely discussed. In this study, the aim of our study was to assess the performance of ASL-MRI in the detection of crossed cerebellar diaschisis after stroke in compared with single-photon emission CT (SPECT). Results 17 of 51(33.3%) patients revealed CCD phenomenon by the SPECT method. In CCD-positive group, CBFASL of ipsilateral cerebellar were significantly increased compared with contralateral cerebellar (p < 0.0001) while no significant differences (p = 0.063, > 0.001) in the CCD-negative group. Positive correlation was detected between admission National institute of health stroke scale (NIHSS) and asymmetry index of SPECT (AISPECT) (r = 0.351, p = 0.011), AIASL (r = 0.372, p = 0.007); infract volume and AISPECT (r = 0.443, p = 0.001), AIASL (r = 0.426, p = 0.002). Significant correlation was also found between cerebral blood flow of SPECT (CBFSPECT) and CBFASL, AISPECT and AIASL (r = 0.204, p = 0.04; r = 0.467, p = 0.001, respectively). Furthermore, the area under the receiver operating characteristic (ROC) curve value of AIASL was 0.829. Conclusions CBF derived from ASL-MRI could be valuable for assessment of CCD in supratentorial stroke patients. Additionally, CCD was significantly associated with larger ischemic volume and higher initial NIHSS score.

Lesson of the month: novel method to quantify neutrophil uptake in early lung cancer using SPECT-CT

Neutrophils play an important role in the lung tumour microenvironment. We hypothesised that radiolabelled neutrophils coupled to single-photon emission CT (SPECT) may non-invasively quantify neutrophil uptake in tumours from patients with non-small cell lung cancer. We demonstrated increased uptake of radiolabelled neutrophils from the blood into tumours compared with non-specific uptake using radiolabelled transferrin. Moreover, indium-111-neutrophil activity in the tumour biopsies also correlated with myeloperoxidase (MPO)-positive neutrophils. Our data support the utility of imaging with In-111-labelled neutrophils and SPECT-CT to quantify neutrophil uptake in lung cancer.